Valine is catabolized in a series of enzyme-catalyzed reactions to succinyl-coenzyme A (succinyl-CoA). Intermediates in this stepwise process include methacrylyl-CoA, 3-hydroxyisobutyryl-CoA (HIB-CoA), and hydroxyisobutyric acid (Shimomura, Y. et al. (1994) J. Biol. Chem. 269:14248-14253).
HIB-CoA hydrolase (also known as 3-hydroxy-2-methylpropanoyl-CoA hydrolase and beta-hydroxyisobutyryl CoA deacylase), an enzyme unique to the valine catabolic pathway, has been purified from rat liver (Shimomura et al., supra). HIB-CoA hydrolase catalyzes the hydrolysis of HIB-CoA to hydroxyisobutyric acid and CoA. The enzyme consists of a single polypeptide of approximately 36 kdal, and is highly specific for HIB-CoA. The high catalytic activity of HIB-CoA hydrolase compared to other enzymes of the valine catabolic pathway suggests that the rapid destruction of HIB-CoA is physiologically important. HIB-CoA is maintained in rapid equilibrium with methacrylyl-CoA by the enzyme crotonase in the preceding step of the valine catabolic pathway. HIB-CoA and methacrylyl-CoA are not detectable in liver cells even under conditions which should maximize the concentrations of valine catabolic intermediates (Corkey, B. E. et al. (1982) J. Biol. Chem. 257:9668-9676). Shimomura et al. suggest that HIB-CoA hydrolase prevents the accumulation of, and protects the cell from, the toxic effects of methacrylyl-CoA.
Methacrylyl-CoA is a highly reactive compound which modifies thiol-containing enzymes and cofactors. Cellular accumulation of methacrylyl-CoA is the hallmark of an inborn error of metabolism known as methacrylic aciduria. This autosomal recessive metabolic disorder arises from a deficiency of HIB-CoA hydrolase. A male infant born with an almost complete lack of HIB-CoA hydrolase exhibited multiple congenital physical malformations, including cardiac, neurological, musculoskeletal and connective tissue abnormalities, and died at 3 months of a cardiac lesion. Brown, G. K. et al. (1982; Pediatrics 70:532-538) suggest that tissue damage arising from reactions between methacrylyl-CoA and sulfhydryl-containing enzymes and cofactors account for the teratogenic effects observed in this patient.
The amino acid sequences of several tryptic peptides of rat HIB-CoA hydrolase and the cDNA and deduced protein sequence of a human HIB-CoA hydrolase were recently reported (Hawes, J. W. et al. (1996) J. Biol. Chem. 271:26430-26434). Northern analysis with various human tissues showed expression of the human HIB-CoA hydrolase predominantly in liver, heart, and kidney.
Infants which are afflicted with an inborn error of metabolism (IEM) frequently remain undiagnosed until late in the course of their illness. Delay in the recognition and treatment of an IEM may have tragic consequences. The acute presentation of an IEM often resembles, and may be misdiagnosed as, more common disorders such as sepsis. Discovery of a human 3-hydroxyisobutyryl-coenzyme A hydrolase and the polynucleotides which encode it satisfies a need in the art by providing new compositions useful in diagnosing and treating the IEM methacrylic aciduria and other disorders associated with cellular accumulation of methacrylyl-CoA.